Oxidative Stress, Type 2 Diabetes
Conditions
Keywords
insulin secretion, beta-cell function, oxidative stress, type 2 diabetes
Brief summary
Insulin is secreted by cells in the pancreas called beta-cells. Beta-cell dysfunction is a critical feature of type 2 diabetes (T2DM). High glucose levels can exacerbate beta-cell dysfunction with oxidative stress proposed as a major mediator of this glucotoxic effect. High glucose levels have also been shown to contribute to vascular dysfunction and inflammation and these adverse responses decreased with the use of antioxidants. The hypothesis is that antioxidants improve beta-cell function in individuals with elevated glucose levels by decreasing oxidative stress. In this study the investigators will specifically test whether the antioxidant N-acetylcysteine (NAC) can improve beta-cell function in individuals with type 2 diabetes by decreasing oxidative stress. This study will be a dose finding study to determine the tolerability of 600 mg versus 1200 mg twice a day of NAC and the effects on beta-cell function, glucose tolerance and oxidative stress markers in persons with type 2 diabetes.
Detailed description
Beta-cell dysfunction is a critical feature of type 2 diabetes (T2DM). High glucose levels can exacerbate beta-cell dysfunction with oxidative stress proposed as a major mediator of this glucotoxic effect. High glucose levels have also been shown to contribute to vascular dysfunction and inflammation and these adverse responses decreased with the use of antioxidants. The hypothesis is that antioxidants improve beta-cell function in individuals with elevated glucose levels by decreasing oxidative stress. In this study the investigators will specifically test whether the antioxidant N-acetylcysteine (NAC) can improve beta-cell function in individuals with type 2 diabetes by decreasing oxidative stress. This initial study will be a dose finding study to determine the tolerability of 600 mg versus 1200 mg twice a day of NAC and the effects of NAC treatment on beta-cell function, glucose tolerance and oxidative stress markers in persons with type 2 diabetes. Study procedures will include a fasting urine sample and performance of a 2 hour 75 gram oral glucose tolerance test at baseline, after 2 weeks on 600 mg twice daily NAC and again after 2 more weeks on 1200 mg NAC twice a day.
Interventions
DRUGN-acetylcysteine
600 mg N-acetylcysteine (NAC) twice daily by mouth for 2 weeks followed by 1200 mg NAC twice daily by mouth for 2 additional weeks.
Sponsors
VA Puget Sound Health Care System
Utzschneider, Kristina, M.D.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Type 2 diabetes
Exclusion criteria
* Pregnant or lactating females * Uncontrolled diabetes mellitus with severe hyperglycemia (hemoglobin A1C ≥ 9%) * Patients with diabetes mellitus who are taking insulin or glucose-lowering agents other than metformin * Chronic oral or parenteral corticosteroid treatment (\>7 consecutive days of treatment) within 8 weeks prior to screening * Use of human immunodeficiency virus (HIV) protease inhibitors or niacin * Chronic inflammatory diseases or use of anti-inflammatory drugs. * Thyroid abnormalities (thyroid-stimulating hormone \[TSH\] \<0.5 or \>5 µU/ml) * Creatinine \>1.5 in men and \>1.3 mg/dl in women * History of dysphagia, gastroparesis, gastric ulcer, malabsorption, swallowing disorders or intestinal motility disorder * Gastroesophageal reflux disease (heartburn) requiring treatment. * Active cancer * Clinical hepatic disease or alanine aminotransferase (ALT) greater than ≥ 1.5 times upper limit of normal within 60 days preceding the first dose of the study drug * Weight loss of \>5% body weight within the last 6 months, or starting an intensive exercise program within 4 weeks of study initiation * Smoke or use tobacco * Excessive alcohol consumption (\>2 drinks a day) * Use of any investigational drug in the last 30 days * Anemia (hematocrit \<33%), donation of one unit (500 ml) or more of blood, significant blood loss equaling at least one unit of blood within the past 2 weeks or a blood transfusion within 8 weeks prior to screening * Employment by the research center
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Fasting Urine F2 Alpha Isoprostane Levels | 4 weeks | Change in fasting urine isoprostane levels at 4 weeks vs baseline as a marker of oxidative stress |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve for Glucose (AUCg) | 4 weeks | Change in AUCg from 0-120 minutes during the oral glucose tolerance test at 4 weeks compared to baseline |
| Oral Disposition Index | 4 weeks | The change in the oral disposition index defined was the change in the early insulin response divided by the change in glucose from 0-30 minutes during the oral glucose tolerance test divided by fasting insulin. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| N-acetylcysteine Dose Study Subjects will take N-acetylcysteine (NAC) 600 mg twice daily for 2 weeks, then 1200 mg twice daily for an additional 2 weeks. Study procedures will be performed at baseline, after 2 weeks and after 4 weeks.
N-acetylcysteine: 600 mg N-acetylcysteine (NAC) twice daily by mouth for 2 weeks followed by 1200 mg NAC twice daily by mouth for 2 additional weeks. | 13 |
| Total | 13 |
Baseline characteristics
| Characteristic | N-acetylcysteine Dose Study |
|---|---|
| Age, Continuous | 53.9 years STANDARD_DEVIATION 11.7 |
| body mass index | 37.3 kg/m2 STANDARD_DEVIATION 10.1 |
| HbA1c | 6.17 % STANDARD_DEVIATION 2.05 |
| metformin | 6 participants |
| Sex: Female, Male Female | 7 Participants |
| Sex: Female, Male Male | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 0 / 13 |
| serious Total, serious adverse events | 0 / 13 |
Outcome results
Primary
Fasting Urine F2 Alpha Isoprostane Levels
Change in fasting urine isoprostane levels at 4 weeks vs baseline as a marker of oxidative stress
Time frame: 4 weeks
Population: Change in urine F2 alpha isoprostanes/mg urine creatinine. Urine isoprostanes were only measured in a subset of participants due to lack of effect of the intervention on glucose tolerance.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine Dose Study | Fasting Urine F2 Alpha Isoprostane Levels | -0.089 ng/ml | Standard Deviation 1.28 |
Secondary
Area Under the Curve for Glucose (AUCg)
Change in AUCg from 0-120 minutes during the oral glucose tolerance test at 4 weeks compared to baseline
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine Dose Study | Area Under the Curve for Glucose (AUCg) | -1011 mg/dl x 120 minutes | Standard Deviation 10922 |
Secondary
Oral Disposition Index
The change in the oral disposition index defined was the change in the early insulin response divided by the change in glucose from 0-30 minutes during the oral glucose tolerance test divided by fasting insulin.
Time frame: 4 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| N-acetylcysteine Dose Study | Oral Disposition Index | -0.08 mg/dl | Standard Deviation 0.18 |